Controlled Release Compositions

ABSTRACT

Controlled release compositions for controlling release of a GnRH molecule or a GnRH analog are provided. The compositions include a GnRH molecule or GnRH analog as an active agent, and a controlled release component for controlling release of the GnRH molecule or GnRH analog from the composition. The compositions provide a sustained mean steady state plasma concentration (C ss ) of the active agent of at least about 1.5 ng/mL for a period of at least about 48 hours when the composition is administered to a subject. In addition, the use of a controlled release component in the manufacture of a composition for the controlled release of a GnRH molecule or GnRH analog is provided. The controlled release component is capable of providing a sustained mean steady state plasma concentration (C ss ) of the active agent of at least about 1.5 ng/mL for a period of at least about 48 hours when the manufactured composition is administered to a subject. The controlled release component can include a polymeric material and/or a non-polymeric material. When the compositions are administered to a subject, for example when implanted, the compositions release the active agent in a controlled fashion. Methods for producing the compositions are also provided, as are methods of using the compositions to provide for controlled release of the GnRH molecule or GnRH analog in a subject.

TECHNICAL FIELD

The present invention is generally in the field of controlled releasecompositions for delivery of peptide or protein biopharmaceuticals, inparticular GnRH or GnRH analog biopharmaceuticals.

BACKGROUND OF THE INVENTION

Biodegradable controlled release systems for active agents are wellknown in the art. Biodegradable matrices for drug delivery are usefulbecause they obviate the need to remove the drug-depleted device.

The most common matrix materials used for controlled release systems arepolymers. The field of biodegradable polymers has developed rapidlysince the synthesis and biodegradability of polylactic acid was reportedby Kulkarni et al. (1966) Arch. Surg. 93:839. Examples of other polymerswhich have been reported as useful as a matrix material for controlledrelease systems include polyanhydrides, polyesters such aspolyglycolides and polylactide-co-glycolides, polyamino acids such aspolylysine, polymers and copolymers of polyethylene oxide, acrylicterminated polyethylene oxide, polyamides, polyarethanes,polyorthoesters, polyacrylonitriles, and polyphosphazenes. See, e.g.,U.S. Pat. Nos. 4,891,225 and 4,906,474 to Langer (polyanhydrides),4,767,628 to Hutchinson (polylactide, polylactide-co-glycolide acid),4,530,840 to Tice, et al. (polylactide, polyglycolide, and copolymers),and 5,234,520 (Dunn et al., biodegradable polymers for controlleddelivery in treating periodontal disease).

Degradable materials of biological origin are well known including, forexample, crosslinked gelatin. Hyaluronic acid has been crosslinked andused as a degradable swelling polymer for biomedical applications (see,e.g., U.S. Pat. No. 4,957,744 and Della Valle et al. (1991) Polym.Mater. Sci. Eng., 62:731-735).

Biodegradable hydrogels have also been developed for use in controlleddelivery systems and serve as carriers of biologically active materialssuch as hormones, enzymes, antibiotics, antineoplastic agents, and cellsuspensions. See, e.g., U.S. Pat. No. 5,149,543. In addition, dispersionsystems are also currently in use as carriers of substances,particularly biologically active compounds. Dispersion systems used forpharmaceutical and cosmetic formulations can be categorized as eithersuspensions or emulsions. Suspensions are comprised of solid particlesranging in size from a few nanometers up to hundreds of microns,dispersed in a liquid medium using suspending agents. Solid particlesinclude microparticles, microcapsules, and the like. Emulsions aregenerally dispersions of one liquid in another stabilized by aninterfacial film of emulsifiers such as surfactants and lipids. Emulsionformulations include water in oil and oil in water emulsions, multipleemulsions, microemulsions, microdroplets, and liposomes. Microdropletsare unilamellar phospholipid vesicles that consist of a spherical lipidlayer with an oil phase inside, for example, those described in U.S.Pat. Nos. 4,622,219 and 4,725,442. Liposomes are phospholipid vesiclesprepared by mixing water-insoluble polar lipids with an aqueoussolution. The unfavorable entropy caused by mixing the insoluble lipidin the water produces a highly ordered assembly of concentric closedmembranes of phospholipid with entrapped aqueous solution.

A number of systems for forming an implant in situ have been described.For example, U.S. Pat. No. 4,938,763 describes a method for forming animplant by dissolving a non-reactive, water insoluble thermoplasticpolymer in a biocompatible, water-soluble solvent to form a liquid,placing the liquid within the body, and allowing the solvent todissipate to produce a solid implant. The polymer solution can be placedin the body via syringe. The implant can assume the shape of itssurrounding cavity. Alternatively, an implant can be formed fromreactive, liquid oligomeric polymers which contain no solvent and whichcure in place to form solids, usually with the addition of a curingcatalyst.

SUMMARY OF THE INVENTION

Controlled release compositions for controlling release of a GnRHmolecule or a GnRH analog are provided. It is thus an object of theinvention to provide a controlled release composition comprising a GnRHmolecule or GnRH analog and a controlled release component forcontrolling release of the GnRH molecule or GnRH analog from thecomposition. The composition is capable of providing a sustained meansteady state plasma concentration (C_(ss)) of the GnRH molecule or GnRHanalog of at least about 1.5 ng/mL for a period of at least about 48hours when the composition is administered to a subject.

It is more particularly an object of the present invention to provide acomposition suitable for establishing therapeutically effective plasmalevels of a GnRH molecule or GnRH analog for a period of at least about48 hours in a subject after administration of the composition, whereinsuch plasma levels are substantially higher than those attained by theuse of commercially available GnRH, or GnRH analog medicaments currentlyemployed in the medical arts. In this regard, the compositions of thepresent invention can be used to establish a sustained mean C_(ss) ofthe GnRH molecule or GnRH analog on the order of at least about 1.5ng/mL for a period of at least about 48 hours when the composition isadministered to a subject, in some compositions, a sustained mean C_(ss)of the GnRH molecule or GnRH analog on the order of at least about 2.0ng/mL or more can be established, in other compositions at least about2.5 ng/mL or more, and in yet further compositions, at least about 3.0to 5.0 ng/mL or more. All of the novel compositions of the presentinvention are capable of providing these high plasma levels for a periodof at least about 48 hours in the subject after administration, in somecompositions, these levels can be established for a period of at leastabout a week or more or at least about 2 weeks or more, and in yetfurther compositions these plasma levels are established for a period ofat least about a month or more.

It is another object of the invention to provide for the use of acontrolled release component in the manufacture of a composition for thecontrolled release of a GnRH molecule or GnRH analog. The controlledrelease component is capable of providing a sustained mean steady stateplasma concentration (C_(ss)) of the GnRH molecule or GnRH analog of atleast about 1.5 ng/mL for a period of at least about 48 hours when thecomposition is administered to a subject.

Here again, it is more particularly an object of the present inventionto provide for the use of a controlled release component in themanufacture of a composition suitable for establishing therapeuticallyeffective plasma levels of a GnRH molecule or GnRH analog for a periodof at least about 48 hours in a subject after administration of thecomposition, wherein such plasma levels are substantially higher thanthose attained by the use of commercially available GnRH, or GnRH analogmedicaments currently employed in the medical arts. Thus, the controlledrelease components can be used to produce compositions capable ofestablishing a sustained mean C_(ss) of the GnRH molecule or GnRH analogon the order of at least about 1.5 ng/mL for a period of at least about48 hours when the composition is administered to a subject, in someuses, the compositions so produced can be used to establish a sustainedmean C_(ss) of the GnRH molecule or GnRH analog on the order of at leastabout 2.0 ng/mL or more, in other uses the compositions can be used toestablish a mean C_(ss) of at least about 2.5 ng/mL or more, and yetfurther compositions can be produced to establish a mean C_(ss) of atleast about 3.0 to 5.0 ng/mL or more. In the practice of the invention,controlled release components can be used to produce composition capableof providing these high plasma levels for a period of at least about 48hours in the subject after administration, in other compositions, thelevels can be established for a period of at least about a week or moreor at least about 2 weeks or more, and in yet further compositions theseplasma levels are established for a period of at least about a month ormore.

The compositions of the present invention can be provided in anysuitable dosage form depending upon the manner in which the compositionwill be administered. In this regard, the present compositions may beprovided as oral dosage forms and administered by oral routes (e.g.,administered as capsules including hard capsules and soft capsules,solid preparations such as granules, tablets, pills, troches orlozenges, cachets, pellets, powders, particulates, microparticulates(and any other particulate form). Alternatively, the presentcompositions can be provided in dosage forms suitable for administrationby non-oral routes (e.g., any parenteral route such as IM(intramuscular), subcutaneous, transdermal, visceral, IV (intravenous),IP (intraperitoneal), intraarterial, intrathecal, intratumoral,perivascular, intracranial, periophthalmic, intrabladder, intravaginal,intraurethral, intrarectal, and adventitial routes, as well as othersuitable dosage forms).

In certain aspects of the invention, the compositions are intended foradministration by implantation, and can thus be provided in a shapedsolid dosage form such as a sphere, rod, slab, film, fiber, needle,cylinder, sheet, tube, particle, or any other suitable geometryincluding microparticles, microspheres, and/or microcapsules. Thecompositions can further be provided in any suitable size and shape ofimplantable device for specialized locations, for example as a uterineimplant, periurethral implant, splint, or stent (formed from,containing, or coated with the composition).

Compositions provided as solid dosage forms suitable for implantationcan be implanted at a desired site surgically, or using minimallyinvasive techniques employing trocars, catheters, etc. The implantabledosage forms can thus be implanted into suitable tissues using standardtechniques, such as where the dosage forms are implanted intradermally,subdermally, subcutaneously, intraperitoneally, intramuscularly, orintralumenally (e.g., intraarterially, intravenously, intravaginally, oreven rectally). The solid dosage forms can alternatively be fabricatedas part of a matrix, graft, prosthetic or coating. If an implantabledosage form is manufactured in particulate form, e.g., as amicroparticle, microsphere or microcapsule, it can then be implantedinto suitable tissue using a cannula, needle and syringe or likeinstrument to inject a suspension of the particles.

In certain other aspects of the invention, the compositions are intendedfor administration by implantation, yet are provided in a dosage formthat is injectable and suitable for forming either a depot or a solid orsemi-solid implant in situ upon or after administration. In this regard,the dosage form can be provided as either a fluid or liquid composition,or as a solid or semi-solid composition that can be rendered into afluid or liquid form by way of addition of suitable solvents and/orplasticizers. These implantable dosage forms can be provided as anemulsion, a paste, a gel, a slurry or a liquid. In certain compositions,one or more solvents/plasticizers added to or present in the compositionare capable of dissipating, diffusing or leaching away from thecomposition upon placement within a biological system, whereby theremaining composition can then coagulate or precipitate to form a depot,semi-solid or solid implant in situ.

With regard to any of the compositions of the present invention that areprovided in a dosage form suitable for administration by implantation,the active agent (the GnRH molecule or GnRH analog) can be generallymixed with the controlled release component to provide a substantiallyhomogeneous composition (e.g., the GnRH molecule or GnRH analog isdistributed uniformly within the controlled release component such as ina monolithic implant dosage form), or the active agent can be coatedwith the controlled release component and provided as a coated solidsuch as a rod, a coaxial rod, a particle, sphere or microsphere dosageform.

In certain aspects of the invention, the composition is provided andadministered as a single dosage form. For example, the composition canbe provided as an implantable solid dosage form such as a rod of fiber.In other aspects, the composition is provided and administered as aplurality of dosage forms. For example, the compositions of theinvention can be provided as a combination of an implantable soliddosage form and an injectable depot. In certain aspects, the compositionis provided as a single dosage form that is administered as a singledosage unit, that is, a single dosage form is used to provide therecited sustained mean steady state plasma concentrations of the GnRHmolecule or GnRH analog. For example, a single solid implantable dosageform such as a rod or fiber can be administered to a subject to providethe desired pharmacokinetics of the present invention. In otherinstances, multiple dosage units of a single dosage form can beadministered to provide the recited sustained mean steady state plasmaconcentrations of the GnRH molecule or GnRH analog, such as wherein aplurality (two or more) of solid implantable dosage forms areadministered either simultaneously, concurrently, or sequentially toprovide the desired pharmacokinetics of the present invention. In yetfurther aspects of the invention, multiple dosage forms, eachrepresenting a single dosage unit, can be administered eithersimultaneously, concurrently, or sequentially to provide the desiredpharmacokinetics of the present invention. Whenever multiple dosageforms and/or units are administered, the actual dose of the GnRHmolecule or GnRH analog in each form or unit can be the same ordifferent. In this way, any desired sustained mean steady state plasmaconcentration of the GnRH molecule or GnRH analog can be achieved in agiven subject by way of administering a single dosage form and/or dosageunit of sufficient dose, or by combining a plurality of dosage formsand/or units containing the same or different dose of the GnRH moleculeor GnRH analog to tailor a specific dose sufficient to establish thedesired plasma concentration in a given subject.

In certain aspects of the invention, the controlled release componentused to produce the controlled release composition comprises a polymermaterial, that is, the controlled release component either contains apolymer material or is comprised substantially of a polymer material. Ina certain compositions, the controlled release component comprises apolymer selected from the group consisting of polyhydroxy acids, such aspoly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s,poly(lactic acid)s, poly(glycolic acid)s, and poly(lacticacid-co-glycolic acid)s, polyanhydrides, polyorthoesters,polyetheresters, polycaprolactone, polyesteramides, polyphosphazines,polycarbonates, polyamides, and copolymers thereof. In a particularcomposition, the controlled release component comprises a polymer thatis an AB copolymer wherein the A component is a copolymer of lactide,glycolide, or caprolactone, and the B component is a polyalkyleneglycol.

In certain other aspects of the invention, the controlled releasecomponent used to produce the controlled release composition comprises anon-polymer material, that is, the controlled release component eithercontains a non-polymer material or is comprised substantially of anon-polymer material. In certain compositions, the controlled releasecomponent comprises a non-polymeric material that is substantiallyinsoluble in water or in an aqueous biological system. In such cases,the composition may further contain a solvent that is dispersible,soluble or miscible in water or in an aqueous system. The solvent maythus be an organic solvent that is capable of dissipating, diffusing orleaching away from the composition upon placement within a biologicalsystem, whereby the carrier can then coagulate or precipitate to form asolid implant in situ.

In yet another aspect of the invention, the non-polymeric material is aliquid carrier material, preferably a high viscosity liquid carriermaterial (“HVLCM”) having a viscosity of at least about 5,000 cP at 37°C. and which does not crystallize neat under ambient or physiologicalconditions. Such liquid carrier materials can be combined with a solventin which the carrier material is soluble. If a HVLCM is used, it ispreferred that the solvent is sufficient to lower the viscosity of theHVLCM. In certain compositions a further material is included that isimmiscible with the non-polymeric material, for example where thecomposition is an emulsion. In these compositions, the non-polymericmaterial may be present in either the dispersed or the continuous phaseof the emulsion.

In each of the compositions of the present invention, the GnRH moleculeor GnRH analog active agent can be present in an amount of at leastabout 10 wt % relative to the total weight of the composition. In othercompositions, the active agent is present in an amount of at least about15 wt %, 20 wt %, 25 wt % or 30 wt % relative to the total weight of thecomposition, or more. In certain aspects of the invention, the totalamount of the GnRH molecule or GnRH analog in the composition (whetheras single or multiple dosage forms and/or units) is between about 1 and50 mg, in other compositions, between about 1.5 and 40 mg, and in stillothers between about 2 and 40 mg, 3 and 35 mg, or between about 5 and 20mg. In certain compositions, the active agent is a GnRH analogue such asdesorelin, tryptorelin, goserelin, and leuprolide.

In certain aspects of the invention, it may be desirable that thecontrolled release composition is constructed such that the GnRHmolecule or GnRH analog active agent is released from the compositionwithout a significant or substantial initial burst. In this regard,certain compositions can be provided wherein less than about 50% of theinitial dose of the active agent is released from the composition withinabout 24 to 48 hours of administration to the subject, in othercompositions, less than about 40% is released in this initial period, instill others, less than about 30% is released. In certain othercompositions of the invention, the GnRH molecule or GnRH analog activeagent is released from the composition without a substantial lag periodor with a minimal lag period. In these same, or in other compositions,the active agent is released in a controlled manner suitable to providefor zero order or linear release kinetics.

It is a further object of the invention to provide a method forestablishing therapeutically effective plasma levels of a GnRH moleculeor GnRH analog for about 48 hours or more in a subject. The methodentails administering any one of the above-described controlled releasecompositions to the subject such that, after administration, thecomposition provides a sustained mean steady state plasma concentration(C_(ss)) of the GnRH molecule or GnRH analog of at least about 1.5 ng/mLfor a period of at least about 48 hours in the subject.

It is more particularly an object of the present invention to provide amethod suitable for establishing therapeutically effective plasma levelsof a GnRH molecule or GnRH analog for a period of at least about 48hours in a subject after administration of the composition, wherein suchplasma levels are substantially higher than those attained by the use ofcommercially available GnRH, or GnRH analog medicaments currentlyemployed in the medical arts. Accordingly, the method of the presentinvention can be used to establish a sustained mean C_(ss) of the GnRHmolecule or GnRH analog on the order of at least about 1.5 ng/mL for aperiod of at least about 48 hours after the composition is administeredto a subject, in some particular methods, a sustained mean C_(ss) of theGnRH molecule or GnRH analog on the order of at least about 2.0 ng/mL ormore can be established, in other methods at least about 2.5 ng/mL ormore, and in yet further methods, at least about 3.0 to 5.0 ng/mL ormore. All of the novel methods of the present invention are capable ofproviding these high plasma levels for a period of at least about 48hours in the subject after administration. In some compositions, theselevels can be established for a period of at least about a week or moreor at least about 2 weeks or more, and in yet further compositions theseplasma levels are established for a period of at least about a month ormore.

In the methods of the invention, the controlled release composition canbe administered using any suitable procedure. Depending upon theselected dosage form(s) and the selected site(s) of administration, thecompositions can be delivered or implanted using minimally invasiveprocedures at a site where release is desired. These procedures caninclude implantation using trocars or catheters, injection usingstandard needle and syringes (of, e.g., powders, particles,microparticles, microspheres, microcapsules), ingrafting or surgical ornon-surgical placement (of, e.g., a matrix, graft, prosthetic orcoating), and the like. The compositions are designed so that the GnRHmolecule or GnRH analog active agent is released in the desired dosageover a defined period of time, and achieves the desired sustained meanC_(ss) for the desired period. In some methods, the compositions can bemanufactured using suitable controlled release components so that theydegrade during and/or after release of the active agent is achieved.

In one preferred method, the composition is formulated to include a GnRHmolecule or GnRH analogue in a solid implant form. The composition isthen administered to a subject in order achieve the target steady stateplasma level, and thereby exert an effect upon the production, function,or activity of a gonadotrophin (LH or FSH) in the subject.

It is an advantage of the present invention that the controlled releasecompositions are able to establish a sustained mean C_(ss) of the GnRHmolecule or GnRH analog on the order of at least about 1.5 ng/mL for aperiod of at least about 48 hours after the composition is administeredto a subject. It is a further advantage of the invention that thecompositions are readily constructed to provide any number of differentpharmaceutical forms, and further to provide a wide range of differentpharmacological release characteristics depending upon the intended siteof administration and medical application.

These and other objects, aspects and advantages of the present inventionwill readily occur to the skilled practitioner upon reading the instantdisclosure, specification and claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to particularlyexemplified controlled release component or process parameters as suchmay, of course, vary. It is also to be understood that the terminologyused herein is for the purpose of describing particular embodiments ofthe invention only, and is not intended to be limiting.

All publications, patents and patent applications cited herein, whethersupra or infra, are hereby incorporated by reference in their entirety.

It must be noted that, as used in this specification and the appendedclaims, the singular forms “a,” “an” and “the” include plural referentsunless the content clearly dictates otherwise. Thus, for example,reference to “a controlled release component” includes a mixture of twoor more such components, reference to “an agent” or “a GnRH activeagent” includes mixtures of two or more such agents, and the like. Inaddition, whenever a specified range is provided in the instantspecification and claims, use of the modifier “about” is applied to allvalues or quantities specified by that range. Thus, the phrase “about 1to 50 mg” means “about 1 to about 50 mg”, and the phrase “about 3.0 to5.0 ng/mL” means “about 3.0 to about 5.0 ng/mL”, and the like.

It is an object of the present invention to provide a controlled releasecomposition comprising a GnRH molecule or GnRH analog as an active agentand a controlled release component for controlling release of the activeagent from the composition. The composition is capable of providing asustained mean steady state plasma concentration (C_(ss)) of the GnRHmolecule or GnRH analog of at least about 1.5 ng/mL for a period of atleast about 48 hours when the composition is administered to a subject.

It is more particularly an object of the present invention to provide acomposition suitable for establishing therapeutically effective plasmalevels of a GnRH molecule or GnRH analog for a period of at least about48 hours in a subject after administration of the composition, whereinsuch plasma levels are substantially higher than those attained by theuse of commercially available GnRH, or GnRH analog medicaments currentlyemployed in the medical arts.

It is another object of the invention to provide for the use of acontrolled release component in the manufacture of a composition for thecontrolled release of a GnRH molecule or GnRH analog. The controlledrelease component is capable of providing a sustained mean steady stateplasma concentration (C_(ss)) of the GnRH molecule or GnRH analog of atleast about 1.5 ng/mL for a period of at least about 48 hours when thecomposition is administered to a subject.

Here again, it is more particularly an object of the present inventionto provide for the use of a controlled release component in themanufacture of a composition suitable for establishing therapeuticallyeffective plasma levels of a GnRH molecule or GnRH analog for a periodof at least about 48 hours in a subject after administration of thecomposition, wherein such plasma levels are substantially higher thanthose attained by the use of commercially available GnRH, or GnRH analogmedicaments currently employed in the medical arts.

It is a still further object of the invention to provide a method forestablishing therapeutically effective plasma levels of a GnRH moleculeor GnRH analog for about 48 hours or more in a subject. The methodentails administering any one of the above-described controlled releasecompositions to the subject such that, after administration, theadministered composition provides a sustained mean steady state plasmaconcentration (C_(ss)) of the GnRH molecule or GnRH analog of at leastabout 1.5 ng/mL for a period of at least about 48 hours in the subject.

Again, it is more particularly an object of the present invention toprovide a method suitable for establishing therapeutically effectiveplasma levels of a GnRH molecule or GnRH analog for a period of at leastabout 48 hours in a subject after administration of the composition,wherein such plasma levels are substantially higher than those attainedby the use of commercially available GnRH, or GnRH analog medicamentscurrently employed in the medical arts.

A number of controlled release compositions for use in long-term, orcontrolled delivery of a GnRH molecule or GnRH analog (a “GnRH active”)are currently available. The vast majority of such compositions employ abiodegradable, implantable polymer system as the controlled releasecomponent, wherein the composition is a solid dosage form such as ashaped implant, or a depot of particles.

GnRH is of central importance to the regulation of fertility. In malesand females, GnRH is released from the hypothalamus into the bloodstreamand travels via the blood to the pituitary, where it induces the releaseof the gonadotropins, luteinizing hormone (“LH”) and folliclestimulating hormone (“FSH”) by gonadotroph cells, and regulatesandrogens, estrogens, and progestins. The key feature of GnRH secretionis pulsatile release, with the frequency or amplitude of GnRH pulsescontrolling whether FSH and/or LH are secreted, and the relative amountsthat are secreted. An important mechanism of action for GnRH analogs(agonists) is the loss of GnRH receptors (due to desensitization) in theplasma membrane of gonadotropes, and the natural down-regulation inresponse to prolonged occupancy of the receptors by the GnRH agonist.

GnRH agonist medicaments have been used to treat a variety of diseasesand conditions, e.g., to treat hormone-dependent cancers (such asprostate cancer); to treat endometriosis; to treat early puberty, tocontrol estrogen production; to treat fertility conditions; and thelike. Some common names and tradenames for commercial GnRH agonistproducts include leuprolide (trade name: Lupron®, Abbott/TAP; Viadur®,Alza), goserelin (trade name: Zoladex®; Zeneca), buserelin (Hoechst),triptorelin (also known as Decapeptyl, D-Trp-6-LHRH and Debiopharm.®.;Ipsen/Beaufour), nafarelin (trade name Synarel®; Syntex), lutrelin(Wyeth), cystorelin (Hoechst), gonadorelin (Ayerst) and histrelin(Ortho), luliberin, desorelin, avorelin, cetrrelix, teverelix,ramorelix, ganirelix, antide, nictide, and azaline.

The most common GnRH analogue medicaments are implantablecontrolled-release formulations based on leuprolide or goserelin, wherethe implants are used to provide 1- to 3-month therapeutic levels of theGnRH active agent in the treatment of prostate cancers or endometriosis.Leuprolide is a generic drug. Lupron contains a water-soluble salt formof the GnRH active (leuprolide acetate) encapsulated by a biodegradablepolymer carrier (polylacticacid “PLA”) to form microspheres. Themicrospheres are freeze-dried, and then administered IM to provide acontrolled release depot implant. Zoladex also contains a water-solublesalt form of the GnRH active agent (goserelin acetate), however theactive agent is dispersed within a biodegradable polymer matrix (D,L-lactic and glycolic acid copolymer “PLGA”) and extruded to form asolid controlled release implant.

Administration of the Lupron or Zoladex controlled release compositionsresults in the following general pharmacokinetics: upon administration,there is typically an initial burst phase, wherein a large amount of theGnRH active is released to provide a maximum plasma concentration(C_(max)) within the first 24 to 48 hours of administration; followed bya steady state phase wherein release of the GnRH active is at leastpartially constant and sufficient to provide a steady state plasmaconcentration (C_(ss)) for a period of from weeks to several months;followed by a tailing off of plasma concentrations. The sustained meansteady state plasma concentration (C_(ss)) of the GnRH molecule or GnRHanalog attained from administration of Lupron during the period of about2 to 16 weeks typically ranges between about 0.2 to 1.0 ng/mL, andtypically around 0.5 ng/mL from the commercial dosage forms that areadministered at 7.5, 22.5 and 30 mg doses. The amount of the GnRH activelost from the Lupron implant during the initial burst is substantial, insome cases approaching up to 50% of the total initial GnRH active dosageprovided. The sustained mean steady state plasma concentration (C_(ss))of the GnRH molecule or GnRH analog attained from administration ofZoladex during the same period is also typically around 0.5 ng/mL. Theselow steady state plasma concentrations are generally considered adequatefor common therapies such as treatment of prostate cancers.

Release of the GnRH actives from the above-described commerciallyavailable controlled release compositions can occur with lags, burstsand other characteristics, that prevent such dosage forms from achievinga substantially constant, zero or first order release profile. This isbecause the GnRH actives are generally not soluble in common hydrophobicpolymer controlled release materials such as DL-polylactide-co-glycolide(“DL-PLG”), and as such must be provided as two-phase compositions inwhich the minor component (e.g. the GnRH active) exists as a dispersedphase within the major component (e.g. the DL-PLG). Due to variousphysical and chemical properties of the controlled release component,the release of the GnRH active from DL-PLGs typically does not occur bysimple diffusion through the polymer matrix. Rather, release occurs bydiffusion through aqueous channels that form when the composition isplaced into an aqueous environment.

Release of the GnRH active from the controlled release composition thusoccurs most usually by diffusion through the aqueous channels formed byhydration of the polymer. The resulting release profile tends to bebiphasic in which two periods of release are separated by a periodduring which little or no peptide release occurs. The “dead” period thatoccurs between the two release phases is particularly problematic forthe GnRH actives, where therapeutic objectives are typically continuoussuppression of one or more gonadotrophic hormone.

One approach to minimize or eliminate the “dead” period involvesincreasing the peptide content of the composition. As the peptidecontent of the composition is increased, inter-particle contact betweenthe peptide particles increases, providing a more extensive network ofpores, and the proportion of peptide that is released during the initialphase increases, in a so-called initial burst phase, ultimatelyconsuming a substantial amount, if not all of the GnRH originallyprovided in the composition. Release typically follows the well-knownHiguchi model for release from a dispersed-drug monolithic device andexhibits square-root-of-time kinetics.

Another approach to minimizing the dead period and achieving a moreconstant release of drug involves the use of polymer compositions thatdegrade relatively rapidly. For example, U.S. Pat. Nos. 4,767,628,5,004,602, 5,366,734 to Hutchinson describe continuous releasecompositions for a GnRH active, wherein the initial diffusion-controlledphase of release and the second degradation-controlled phase of releaseare made to overlap by careful choice of the monomer ratio and themolecular weight of the DL-PLG.

Still another approach involves the use of biodegradable hydrogels sothat the permeability of the peptide (e.g., the GnRH active) in thepolymer matrix is significantly increased. For example, U.S. Pat. Nos.4,526,938 and 4,942,035 to Churchill describe continuous releasecompositions comprising a GnRH active and an amphipathic block copolymerin which the hydrophobic component is biodegradable and the hydrophiliccomponent may or may not be biodegradable. Generally, these compositionscontain relatively large amounts of the hydrophilic component such thatthe resulting polymers are hydrogels capable of absorbing large amountsof water.

U.S. Pat. No. 6,159,490 to Deghenghi describes a method for producingimplants for delivery of a GnRH active (i.e., the GnRH analogleuprolide) from copolymers of lactide and glycolide for periods of from1 to 12 months. Deghenghi's process involves a wet granulation processto combine the GnRH active with the polymer controlled releasecomponent. U.S. Pat. No. 6,217,893 to Pellet et al. describes controlledrelease compositions containing a GnRH active, using polymer orcopolymer controlled release components (lactide and glycolide having ahydrophilic character. No examples of the preparation of or release fromimplants are given.

Although these and other approaches to producing controlled releasecompositions for a GnRH active may have been sufficient to reduceerratic or widely variable release kinetics, the art has heretofore notconsidered how to produce a composition in accordance with the presentinvention, that is, a composition capable of providing substantiallyhigher sustained mean steady state plasma concentrations (C_(ss)) of theGnRH molecule or GnRH analog in the range of the compositions of thepresent invention wherein it is desired to establish steady state plasmaconcentrations of at least about 1.5 ng/mL for a period of at leastabout 48 hours in the subject, in some cases on the order of at leastabout 2.0 ng/mL or more, in others at least about 2.5 ng/mL or more, andyet further cases at least about 3.0 to 5.0 ng/mL or more. Furthermore,the art has heretofore not considered how to produce a composition inaccordance with the present invention that is capable of providing thesenovel high plasma levels for a period of at least about 48 hours in thesubject after administration, in other cases for a period of at leastabout a week or more or at least about 2 weeks or more, and in yetfurther cases these novel high plasma levels can be established for aperiod of at least about a month or more.

In addition, the art has heretofore not considered how to produce acomposition in accordance with the present invention (capable ofproviding these novel high plasma levels for the recited periods),wherein the composition further serves to reduce or eliminate highlyvariable release kinetics during steady state conditions, for example,compositions that release the GnRH active agent at a high level over aprolonged period of time, and that provide more controlled zero-order orlinear release kinetics rather than biphasic release kinetics.

In this regard, compositions produced in accordance with the presentinvention can provide a high sustained mean steady state plasmaconcentrations (C_(ss)) of the GnRH molecule or GnRH analog, and furtherenable a more constant or linear rate of release of the active agent.Such compositions can be provided as a monolithic implant prepared witha hydrolytically biodegradable hydrophobic polymer such as poly(DL-lactide-co-glycolide), DL-PLG, which incorporates a small amount ofhydrophilic polymer. The use of hydrophobic polymers such as PLGs withincorporation of small amounts of hydrophilic polymer such as poly(ethylene glycol), PEG, preferably covalently linked into thehydrophobic polymer backbone provides particularly beneficial releaseprofiles. In addition, the combination of such material choices with asimple process involving, for example, dry blending, compounding(first-pass extrusion), grinding, and re-extrusion, can further providefor beneficial release profiles. The monolithic implant compositions canbe any shaped article such as a rod, needle, film, sphere, cylinder,sheet, or other geometry including microparticles, microspheres, and/ormicrocapsules. A preferred manufacturing process avoids the use ofsolvent to mix the polymeric controlled release component with the GnRHactive. The exemplary composition is designed to provide monophasicrelease, i.e., where release is typically linear or zero order, but mayinclude continuous release where the initial “burst” or “lag” effect isminimal or not present.

The phrase “without an initial burst,” as used herein, intends that theparticular controlled release composition being referred to does notrelease a substantial amount of the GnRH active from the compositionupon normal administration that becomes pharmacologically available inan appreciable amount during a predetermined initial period. Thepresence and level of an initial burst of a GnRH agent from a givencomposition can be readily determined by the skilled artisan employingstandard pharmacological testing techniques well known in the art.Suitable in vitro burst release characterization methods include the USPII Paddle Method, using standard buffer, mixing and heat conditions. Theburst release characteristics of a given composition can also readily bedetermined using standard in vivo testing, such as by monitoring plasmaconcentrations of the GnRH agent in an animal subject, over a given timeperiod. In the compositions of the present invention, preferably lessthan about 40 to 60% of the GnRH agent is released within the first 24to 48 hours after administration, more preferably less than about 30 to50%, and even more preferably less than about 20 to 40% is releasedwithin this initial time period.

I. Materials and Compositions

A. GnRH Active Agents

Essentially any GnRH active agent can be combined with a suitablecontrolled release component to form a composition (and subsequentdosage form) according to the present invention using conventionalprocesses including those methods described herein. Accordingly, as usedherein a “GnRH active” or “GnRH active agent” can include any GnRHmolecule or GnRH analog which, when administered to an organism (humanor animal subject) induces a desired pharmacologic and/or physiologiceffect by local and/or systemic action. The GnRH active is typicallyreferred to as a peptide or protein biopharmaceutical. As used herein,the term “protein” includes peptides, polypeptides, consensus molecules,analogs, derivatives or combinations thereof. The term thus encompassesrecombinant or naturally occurring molecules, whether human or animal inorigin, including naturally occurring, synthetic, semi-synthetic orrecombinantly produced GnRH molecules or GnRH analogs.

As used herein, the term “GnRH analog” is intended to encompass peptidiccompounds that mimic the structure of luteinizing hormone releasinghormone. A GnRH analog may be a GnRH agonist.

As used herein, a “GnRH agonist” is intended to refer to a compound thatstimulates the GnRH receptor such that release of luteinizing hormoneand/or FSH is stimulated. Examples of GnRH agonists include leuprolide(trade name: Lupron®, Abbott/TAP; Viadur®, Alza), goserelin (trade name:Zoladex®; Zeneca), buserelin (Hoechst), triptorelin (also known asDecapeptyl, D-Trp-6-LHRH and Debiopharm.®.; Ipsen/Beaufour), nafarelin(trade name Synarel®; Syntex), lutrelin (Wyeth), cystorelin (Hoechst),gonadorelin (Ayerst) and histrelin (Ortho), luliberin, desorelin,avorelin, cetrrelix, teverelix, ramorelix, ganirelix, antide, nictide,and azaline. Leuprolide agonists are particularly preferred for use inthe compositions of the present invention.

In the practice of the invention, the GnRH active is combined with acontrolled release component to form a controlled release composition.

B. Polymer Controlled Release Components

The compositions disclosed herein can be produced using a variety ofbiocompatible and biodegradable polymer controlled release components.“Biodegradable”, as defined herein, means the polymer will degrade orerode in vivo to form smaller chemical species, wherein the degradationcan result, for example, from enzymatic, chemical, and physicalprocesses. In certain preferred compositions, the polymer controlledrelease component is substantially hydrophobic and degrades byhydrolysis. The term “biocompatible” is used herein to refer to apolymer and any degradation products of the polymer that present nosignificant, deleterious or untoward effects on the recipient's, thatis, the subject's body.

Examples of biodegradable polymers and oligomers suitable for use in thecompositions and methods of the present invention include, but are notlimited to: poly(lactide)s; poly(glycolide)s;poly(lactide-co-glycolide)s; poly(lactic acid)s; poly(glycolic acid)s;and poly(lactic acid-co-glycolic acid)s; poly(caprolactone)s; poly(malicacid)s; polyamides; polyanhydrides; polyamino acids; polyorthoesters;polyetheresters; polycyanoacrylates; polyphosphazines;polyphosphoesters; polyesteramides; polydioxanones; polyacetals;polyketals; polycarbonates; polyorthocarbonates; degradablepolyurethanes; polyhydroxybutyrates; polyhydroxyvalerates; polyalkyleneoxalates; polyalkylene succinates; chitins; chitosans; oxidizedcelluloses; and copolymers, terpolymers, blends, combinations ormixtures of any of the above materials.

As used herein, “hydrophobic” refers to a polymer that is substantiallynot soluble in water. As used herein, “hydrophilic” refers to a polymerthat may be water-soluble or to a polymer having affinity for absorbingwater, but typically not when covalently linked to the hydrophobiccomponent as a co-polymer, and which attracts water.

Hydrophilic polymers suitable for use herein can be obtained fromvarious commercial, natural or synthetic sources well known in the art.Suitable hydrophilic polymers include, but are not limited to:polyanions including anionic polysaccharides such as alginate; agarose;heparin; polyacrylic acid salts; polymethacrylic acid salts; ethylenemaleic anhydride copolymer (half ester); carboxymethyl amylose;carboxymethyl cellulose; carboxymethyl dextran; carboxymethyl starch;carboxymethyl chitin/chitosan; carboxy cellulose;2,3-dicarboxycellulose; tricarboxycellulose; carboxy gum arabic; carboxycarrageenan; carboxy pectin; carboxy tragacanth gum; carboxy xanthangum; carboxy guar gum; carboxy starch; pentosan polysulfate; curdlan;inositol hexasulfate; beta.-cyclodextrin sulfate; hyaluronic acid;chondroitin-6-sulfate; dermatan sulfate; dextran sulfate; heparinsulfate; carrageenan; polygalacturonate; polyphosphate;polyaldehydro-carbonic acid; poly-1-hydroxy-1-sulfonate-propen-2;copolystyrene maleic acid; mesoglycan; sulfopropylated polyvinylalcohols; cellulose sulfate; protamine sulfate; phospho guar gum;polyglutamic acid; polyaspartic acid; polyamino acids; and anyderivatives or combinations thereof. One skilled in the art willappreciate other hydrophilic polymers that are also within the scope ofthe present invention.

Various water-soluble polymers suitable for use herein include, but arenot limited to: poly (alkyleneglycol), polyethylene glycol (“PEG”);propylene glycol; ethylene glycol/propylene glycol copolymers;carboxylmethylcellulose; dextran; polyvinyl alcohol (“PVOH”); polyvinylpyrolidone; poly (alkyleneamine)s; poly (alkyleneoxide)s;poly-1,3-dioxolane; poly-1,3,6-trioxane; ethylene/maleic anhydridecopolymers; polyaminoacids; poly (n-vinyl pyrolidone); polypropyleneoxide/ethylene oxide copolymers; polyoxyethylated polyols; polyvinylalcohol succinate; glycerine; ethylene oxides; propylene oxides;poloxamers; alkoxylated copolymers; water soluble polyanions; and anyderivatives or combinations thereof. In addition, the water-solublepolymer may be of any suitable molecular weight, and may be branched orunbranched.

In certain contemplated compositions of the invention, a hydrophobicpolymer component is co-polymerized with a hydrophilic polymer, ormonomers, to yield a polymeric controlled release system, mostpreferably a block copolymer, or blended with a hydrophilic polymer toyield a blended polymeric controlled release system. These resultantpolymer systems are characterized as having a small amount ofhydrophilic character, but they will not form a hydrogel followingimmersion in an aqueous system. For example, certain polymer systems foruse in the compositions of the present invention may contain awater-soluble polymer such as polyethylene glycol (PEG) in amountstypically up to 25 to 30 wt %, not imparting the hydrogel propertiescited by Churchill but producing devices that exhibit monophasic orzero-order or near zero-order release kinetics. If a PEG is used in thesystem, the preferred molecular weight may be between about 700 Da andabout 500 kDa. Other particularly preferred hydrophilic polymers for usein the polymeric controlled release systems of the invention includepolyvinyl pyrolidone, polyvinyl alcohols, poly (alkyleneamine)s and poly(alkyleneoxide)s.

As used herein, “polymer” and “polymer system” include copolymers andblends unless otherwise expressly defined. Such polymeric materials canbe produced using standard copolymerization techniques, such as graftcopolymerisation, polycondensation and polyaddition, optionally with anappropriate catalyst. These techniques can be carried out inconventional manner well known in the polymer art as regards to time andtemperature. Alternatively, the polymeric controlled release componentscan be produced using standard blending techniques of polymers orblending of copolymers, again carried out in conventional manner wellknown in the polymer art as regards to time and temperature.

The polymer controlled release component, method of manufacture, andGnRH active loading can be selected such that the composition does notform a hydrogel when contacted with or immersed in an aqueous system,for example, when a solid dosage form controlled release composition isimplanted in vivo into an animal or human subject. The polymer systemsused as the controlled release component are characterized by a reducedhydrophobicity relative to the pure hydrophobic polymer component byvirtue of the inclusion of the hydrophilic component. This facilitatesuptake of water by the composition and dissolution and release of theincorporated GnRH active agent, avoiding a lag period and leading tolinear or near zero order release kinetics.

As used herein, the term “hydrogel” is used in its usual manner withinthe art, for example to refer to a polymer material or polymer systemthat swells in the presence of water or other aqueous system, shrinks inthe absence or reduction of the amount of water, is able to retain asignificant fraction of water within its structure, and typically doesnot dissolve in water. One skilled in the art will appreciate that thereare a number of standard tests that one can employ in order to determineif a polymer or polymer system will act as a hydrogel, e.g., form ahydrogel, when immersed in an aqueous system such as when it isimplanted in vivo into an animal or human subject.

The polymeric controlled release component and GnRH active agent may becombined with one or more additional component, for examplepharmaceutically acceptable excipient materials that can act asdispersing agents, bulking agents, binders, carriers, stabilizers,glidants, antioxidants, pH adjusters, anti-irritants, and the like. Theskilled artisan will appreciate that certain excipient materials canserve several of the above-referenced functions in any particularformulation. Thus, any number of suitable excipient materials can bemixed with or incorporated into the compositions of the presentinvention to provide bulking properties, alter GnRH active agent releaserates, increase or impede water uptake, control pH, provide structuralsupport, facilitate manufacturing processes and other uses known tothose skilled in the art. The term “excipient” generally refers to asubstantially inert material that is nontoxic and does not interact withother components of the composition in a deleterious manner. Theproportions in which a particular excipient may be present in thecomposition depend upon the purpose for which the excipient is providedand the identity of the excipient.

For example, suitable excipients that can also act as stabilizers forpeptides such as GnRH molecules and GnRH analogs include pharmaceuticalgrades of dextrose, sucrose, lactose, trehalose, mannitol, sorbitol,inositol, dextran, and the like. Such materials may thus be a saccharidesuch as a monosaccharide, a disaccharide, a polysaccharide or a sugaralcohol. Other suitable excipients include starch, cellulose, sodium orcalcium phosphates, calcium sulfate, citric acid, tartaric acid,glycine, and combinations thereof. Examples of hydrophobic excipientsthat can be added to the controlled release compositions to slowhydration and dissolution kinetics include fatty acids andpharmaceutically acceptable salts thereof (e.g., magnesium stearate,steric acid, zinc stearate, palimitic acid, and sodium palitate).

It may also be useful to employ a charged lipid and/or detergentexcipient in the compositions of the present invention. Suitable chargedlipids include, without limitation, phosphatidylcholines (lecithin), andthe like. Detergents will typically be a nonionic, anionic, cationic oramphoteric surfactant. Examples of suitable surfactants include, forexample, Tergitol® and Triton® surfactants (Union Carbide Chemicals andPlastics); polyoxyethylenesorbitans, e.g., TWEEN® surfactants (AtlasChemical Industries); polysorbates; polyoxyethylene ethers, e.g. Brij;pharmaceutically acceptable fatty acid esters, e.g., lauryl sulfate andsalts thereof; ampiphilic surfactants (glycerides, etc.); and likematerials.

Other excipient materials can be added to the compositions to alterporosity, for example, materials like sucrose, dextrose, sodiumchloride, sorbitol, lactose, polyethylene glycol, mannitol, fructose,polyvinyl pyrrolidone or appropriate combinations thereof. Additionally,the GnRH active agents may be dispersed with oils (e.g., sesame oil,corn oil, vegetable), or a mixture thereof with a phospholipid (e.g.,lecitin), or medium chain fatty acid triglycerides (e.g., Miglyol 812)to provide an oily suspension.

Still further excipeint materials that can be incorporated into thecompositions of the present invention include diluents of various buffercontent (e.g., Tris-HCl, acetate); pH and ionic strength alteringagents; additives such as antioxidants (e.g., ascorbic acid,glutathione, sodium metabisulfite); preservatives (e.g., Thimersol,benzyl alcohol, methyl paraben, propyl paraben); and dispersing agentssuch as water-soluble polysaccharides (e.g., mannitol, lactose, glucose,starches), hyaluronic acid, glycine, fibrin, collagen and inorganicsalts (e.g., sodium chloride).

C Non-Polymer Controlled Release Components

The controlled release compositions disclosed herein can alternativelybe produced using a variety of biocompatible and biodegradablenon-polymer controlled release components. “Biodegradable”, as definedherein, means the non-polymer material will degrade or erode in vivo toform smaller chemical species, wherein the degradation can result, forexample, from enzymatic, chemical, and physical processes. The term“biocompatible” is used herein to refer to a non-polymer material andany degradation products of that material that present no significant,deleterious or untoward effects on the recipient's, that is, thesubject's body.

Selection of a suitable non-polymeric controlled release component iswithin the general skill in the art, using the teaching and guidanceprovided by the instant disclosure and specification. For example,numerous pharmaceutically acceptable non-polymeric carrier systems areavailable to the skilled artisan to produce liquid, spray, cream,lotion, ointment, gel, slurry, oil, emulsion, microemulsion, solid,plaster, film, particle, microparticle, powder or other suitablepharmaceutical dosage forms. These and other carrier systems aredescribed, for example, in Remington's Pharmaceutical Sciences, 16^(th)Edition, 1980 and 17^(th) Edition, 1985, both published by MackPublishing Company, Easton, Pa.

The controlled release compositions of the present invention may furtherinclude one or more additional component, for example pharmaceuticallyacceptable excipient materials that can act as dispersing agents,bulking agents, binders, carriers, stabilizers, glidants, antioxidants,pH adjusters, anti-irritants, and the like. The skilled artisan willappreciate that certain excipient materials can serve several of theabove-referenced functions in any particular formulation. Thus, anynumber of suitable excipient materials can be mixed with or incorporatedinto the controlled release compositions of the present invention toprovide bulking properties, alter the GnRH active agent release rates,increase or impede water uptake, control pH, provide structural support,facilitate manufacturing processes and other known uses. The proportionsin which a particular excipient may be present in the composition dependupon the purpose for which the excipient is provided and the identity ofthe excipient.

For example, suitable excipients that can also act as stabilizers forthe GnRH active agent include pharmaceutical grades of dextrose,sucrose, lactose, trehalose, mannitol, sorbitol, inositol, dextran, andthe like. Such stabilizers may thus be a saccharide such as amonosaccharide, a disaccharide, a polysaccharide or a sugar alcohol.Other suitable excipients include starch, cellulose, sodium or calciumphosphates, calcium sulfate, citric acid, tartaric acid, glycine, andcombinations thereof. Examples of hydrophobic excipients that can beadded to slow hydration and dissolution kinetics include fatty acids andpharmaceutically acceptable salts thereof (e.g., magnesium stearate,steric acid, zinc stearate, palimitic acid, and sodium palitate).

It may also be useful to employ a charged lipid and/or detergentexcipient in addition to the non-polymer controlled release component.Suitable charged lipids include, without limitation,phosphatidylcholines (lecithin), and the like. Detergents will typicallybe a nonionic, anionic, cationic or amphoteric surfactant. Examples ofsuitable surfactants include, for example, Tergitol® and Triton®surfactants (Union Carbide Chemicals and Plastics);polyoxyethylenesorbitans, e.g., TWEEN® surfactants (Atlas ChemicalIndustries); polysorbates; polyoxyethylene ethers, e.g. Brij;pharmaceutically acceptable fatty acid esters, e.g., lauryl sulfate andsalts thereof; ampiphilic surfactants (glycerides, etc.); and likematerials.

Other excipient materials can be added to alter porosity of thenon-polymer controlled release component, for example, materials likesucrose, dextrose, sodium chloride, sorbitol, lactose, polyethyleneglycol, mannitol, fructose, polyvinyl pyrrolidone or appropriatecombinations thereof. Additionally, the GnRH active may be dispersedwith oils (e.g., sesame oil, corn oil, vegetable), or a mixture thereofwith a phospholipid (e.g., lecitin), or medium chain fatty acidtriglycerides (e.g., Miglyol 812) to provide an oily suspension.

Still further excipeint materials that can be incorporated into thecompositions of the present invention include diluents of various buffercontent (e.g., Tris-HCl, acetate); pH and ionic strength alteringagents; additives such as antioxidants (e.g., ascorbic acid,glutathione, sodium metabisulfite); preservatives (e.g., Thimersol,benzyl alcohol, methyl paraben, propyl paraben); and dispersing agentssuch as water-soluble polysaccharides (e.g., mannitol, lactose, glucose,starches), hyaluronic acid, glycine, fibrin, collagen and inorganicsalts (e.g., sodium chloride).

In certain embodiments of the invention, the non-polymeric controlledrelease component is substantially insoluble in water or in an aqueousbiological system. Exemplary such non-polymeric carrier materialsinclude, but are not limited to: sterols such as cholesterol,stigmasterol, β-sitosterol, and estradiol; cholestery esters such ascholesteryl stearate; C₁₂-C₂₄ fatty acids such as lauric acid, myristicacid, palmitic acid, stearic acid, arachidic acid, behenic acid, andlignoceric acid; C₁₈-C₃₆ mono-, di- and triacylglycerides such asglyceryl monooleate, glyceryl monolinoleate, glyceryl monolaurate,glyceryl monodocosanoate, glyceryl monomyristate, glycerylmonodicenoate, glyceryl dipalmitate, glyceryl didocosanoate, glyceryldimyristate, glyceryl didecenoate, glyceryl tridocosanoate, glyceryltrimyristate, glyceryl tridecenoate, glycerol tristearate and mixturesthereof; sucrose fatty acid esters such as sucrose distearate andsucrose palmitate; sorbitan fatty acid esters such as sorbitanmonostearate, sorbitan monopalmitate and sorbitan tristearate; C₁₆-C₁₈fatty alcohols such as cetyl alcohol, myristyl alcohol, stearyl alcohol,and cetostearyl alcohol; esters of fatty alcohols and fatty acids suchas cetyl palmitate and cetearyl palmitate; anhydrides of fatty acidssuch as stearic anhydride; phospholipids including phosphatidylcholine(lecithin), phosphatidylserine, phosphatidylethanolamine,phosphatidylinositol, and lysoderivatives thereof; sphingosine andderivatives thereof; spingomyelins such as stearyl, palinitoyl, andtricosanyl spingomyelins; ceramides such as stearyl and palmitoylceramides; glycosphingolipids; lanolin and lanolin alcohols; andcombinations and mixtures thereof. Certain preferred non-polymericcarriers include cholesterol, glyceryl monostearate, glyceroltristearate, stearic acid, stearic anhydride, glyceryl monocleate,glyceryl monolinoleate, and acetylated monoglycerides.

If one or more of the above-noted non-polymeric controlled releasecomponents is selected for use in a composition of the presentinvention, it will typically be combined with a compatible and suitableorganic solvent for the non-polymeric material to form a compositionhaving a consistency ranging from watery to viscous to a spreadableputty or paste. The consistency of the composition will vary accordingto factors such as the solubility of the non-polymeric material in thesolvent, the concentration of the non-polymeric material, theconcentration of the GnRH active, additives and excipients. Thesolubility of a non-polymeric material in a particular solvent will varyaccording to factors such as its crystallinity, hydrophilicity, ioniccharacter and lipophilicity. Accordingly, the ionic character and theconcentration of the non-polymeric material in the solvent can beadjusted to achieve the desired solubility. Preferred non-polymericmaterials for use as the controlled release component are those thathave low crystallinity, nonpolar characteristics, and are morehydrophobic.

Suitable organic solvents for use in the compositions are generallythose that are biocompatible, pharmaceutically acceptable, and will atleast partially dissolve the selected non-polymeric material. Theorganic solvent will further have a solubility in water ranging frommiscible to soluble to dispersible. In certain compositions, the solventis selected such that it is capable of diffusing, dispersing, orleaching away from the composition in situ in an aqueous system and intofluids found at the administration site, thereby forming a solidimplant. Preferably, the non-polymeric material solidifies in situ toform a solid matrix within about 1-5 days after administration(implantation), preferably within about 1-3 days, preferably withinabout 2 hours. In addition, the solvent preferably has a Hildebrand(HLB) solubility ratio of from about 9-13 (cal/cm³)^(1/2), and thedegree of polarity of the solvent is effective to provide at least about5% solubility in water.

Suitable organic solvents thus include, but are not limited to:substituted heterocyclic compounds such as N-methyl-2-pyrrolidone (NMP)and 2-pyrrolidone (2-pyrol); esters of carbonic acid and alkyl alcoholssuch as propylene carbonate, ethylene carbonate and dimethyl carbonate;fatty acids such as acetic acid, lactic acid and heptanoic acid; alkylesters of mono-, di-, and tricarboxylic acids such as 2-ethyoxyethylacetate, ethyl acetate, methyl acetate, ethyl lactate, ethyl butyrate,diethyl malonate, diethyl glutonate, tributyl citrate, diethylsuccinate, tributyrin, isopropyl myristate, dimethyl adipate, dimethylsuccinate, dimethyl oxalate, dimethyl citrate, triethyl citrate, acetyltributyl citrate, glyceryl triacetate; alkyl ketones such as acetone andmethyl ethyl ketone; ether alcohols such as 2-ethoxyethanol, ethyleneglycol dimethyl ether, glycofurol and glycerol formal; alcohols such asethanol and propanol; polyhydroxy alcohols such as propylene glycol,polyethylene glycol (PEG), glycerin (glycerol), 1,3-butyleneglycol, andisopropylidene glycol (2,2-dimethyl-1,3-dioxolone-4-methanol); Solketal;dialkylamides such as dimethylformamide, dimethylacetamide;dimethylsulfoxide (DMSO) and dimethylsulfone; tetrahydrofuran; lactonessuch as ε-caprolactone and butyrolactone; cyclic alkyl amides such ascaprolactam; aromatic amides such as N,N-dimethyl-m-toluamide, and1-dodecylazacycloheptan-2-one; and the like; and mixtures andcombinations thereof. Preferred solvents include N-methyl-2-pyrrolidone,2-pyrrolidone, dimethylsulfoxide, ethyl lactate, propylene carbonate,glycofurol, glycerol formal, and isopropylidene glycol.

The organic solvent can be provided in the composition in an amount offrom about 99.5 to about 1 percent by weight relative to the totalweight of the composition (wt %), in an amount of from about 95 to 10 wt%, in an amount of from about 75 to 25 wt %, or in an amount of fromabout 60 to 40 wt %, depending upon the selected non-polymericcontrolled release component, organic solvent, GnRH active, additiveand/or excipient being used in the composition.

A number of suitable additives may be included with the non-polymercontrolled release component in order to impart selected characteristicsupon the composition. For example, the may include a minor amount of abiodegradable thermoplastic polymer such as a polylactide,polycaprolactone, polyglycolide, or copolymer thereof, in order toprovide a more coherent solid implant or a composition with greaterviscosity so as to hold it in place while it solidifies. Suchthermoplastic polymers are disclosed in U.S. Pat. No. 4,938,763 to Dunnet al.

Optionally, a pore-forming agent can be included in the composition. Thepore-forming agent can be any organic or inorganic,pharmaceutically-acceptable substance that is substantially soluble inwater or body fluid, and will dissipate from the non-polymericcontrolled release component material and/or the solid matrix of animplant into surrounding body fluid at the implant site. Thepore-forming agent may preferably be insoluble in the organic solvent toform a uniform mixture with the non-polymeric material. The pore-formingagent may also be a water-immiscible substance that rapidly degrades toa water-soluble substance. In certain compositions, the pore-formingagent is combined with the non-polymeric material and organic solvent inadmixture. Suitable pore-forming agents that can be used in thecomposition include, for example, sugars such as sucrose and dextrose,salts such as sodium chloride and sodium carbonate, polymers such ashydroxylpropylcellulose, carboxymethylcellulose, polyethylene glycol andpolyvinylpyrrolidone, and the like. Solid crystals that will provide adefined pore size, such as salt or sugar, are preferred.

In other embodiments of the present invention, compositions are providedwherein the non-polymeric controlled release component is a liquid. Theliquid non-polymeric material is preferably a high viscosity liquidcarrier material (“HVLCM”), that is non-water soluble, and has aviscosity of at least 5,000 cP, (and optionally at least 10,000, 15,000;20,000; 25,000 or even 50,000 cP) at 37° C. and does not crystallizeneat under ambient or physiological conditions. The term “non-watersoluble” refers to a material that is soluble in water to a degree ofless than one percent by weight under ambient conditions. In theparticular context of these liquid carrier materials, the term“non-polymeric” refers to esters or mixed esters having essentially norepeating units in the acid moiety of the ester, as well as esters ormixed esters having acid moieties wherein functional units in the acidmoiety are repeated a small number of times (i.e., oligomers).Generally, liquid materials having more than five identical and adjacentrepeating units or mers in the acid moiety of the ester are excluded bythe term “non-polymeric” as used herein, but materials containingdimers, trimers, tetramers, or pentamers are included within the scopeof this term. When the ester is formed from hydroxy-containingcarboxylic acid moieties that can further esterify, such as lactic acidor glycolic acid, the number of repeat units is calculated based uponthe number of lactide or glycolide moieties, rather than upon the numberof lactic acid or glycolic acid moieties, where a lactide repeat unitcontains two lactic acid moieties esterified by their respective hydroxyand carboxy moieties, and where a glycolide repeat unit contains twoglycolic acid moieties esterified by their respective hydroxy andcarboxy moieties. Esters having 1 to about 20 etherified polyols in thealcohol moiety thereof, or 1 to about 10 glycerol moieties in thealcohol moiety thereof, are considered non-polymeric as that term isused herein.

In certain compositions of the present invention, the HVLCM decreases inviscosity, in some cases significantly, when mixed with a solvent toform a low viscosity liquid carrier material (“LVLCM”) that can beadministered using standard medical devices. The LVLCM composition istypically easier to place in the body than a HVLCM composition, becauseit flows more easily into and out of syringes or other implantationmeans. It also can easily be formulated as an emulsion. The LVLCM canhave any desired viscosity, but its viscosity is generally lower thanthe corresponding HVLCM. As an example, viscosity ranges for the LVLCMof less than approximately 6,000 cP, less than approximately 4,000 cP,less than approximately 1,000 cP, or less than 200 cP, are typicallyuseful for in vivo applications.

The particular non-polymeric HVLCM controlled release component used inthe compositions of the invention can be one or more of a variety ofmaterials. Suitable materials include nonpolymeric esters or mixedesters of one or more carboxylic acids. In a particular composition, theester is formed from carboxylic acids that are esterified with a polyolhaving from about 2 to about 20 hydroxy moieties, and which may include1 to about 20 etherified polyols. Particularly suitable carboxylic acidsfor forming the acid moiety of the ester of the HVLCM include carboxylicacids having one or more hydroxy groups, e.g., those obtained by ringopening alcoholysis of lactones, or cyclic carbonates or by thealcoholysis of carboxylic acid anhydrides. Amino acids are also suitablefor forming esters with the polyol. In a particular composition, theester or mixed ester contains an alcohol moiety having one or moreterminal hydroxy moieties that have been esterified with one or morecarboxylic acids obtained by alcoholysis of a carboxylic acid anhydride,such as a cyclic anhydride.

Nonlimiting examples of suitable carboxylic acids that can be esterifiedto form the HVLCM non-polymeric controlled release component includeglycolic acid, lactic acid, ε-hydroxycaproic acid, serine, and anycorresponding lactones or lactams, trimethylene carbonate, anddioxanone. The hydroxy-containing acids may themselves be furtheresterified through the reaction of their hydroxy moieties withadditional carboxylic acid, which may be the same as or different fromother carboxylic acid moieties in the material. Suitable lactonesinclude, but are not limited to, glycolide, lactide, ε-caprolactone,butyrolactone, and valerolactone. Suitable carbonates include but arenot limited to trimethylene carbonate and propylene carbonate.

In a particular embodiment, the HVLCM non-polymeric controlled releasecomponent may be sucrose acetate isobutyrate (SAIB) or some other esterof a sugar alcohol moiety with one or more alkanoic acid moieties.

In those compositions where the HVLCM non-polymeric controlled releasecomponent is mixed with a viscosity-lowering solvent to form a LVLCM,the solvents can be water soluble, non-water soluble, or water miscible,and can include, acetone, benzyl alcohol, benzyl benzoate,N-(betahydroxyethyl) lactamidebutylene glycol, caprolactam,caprolactone, corn oil, decylmethylsulfoxide, dimethyl ether, dimethylsulfoxide, 1-dodecylazacycloheptan-2-one, ethanol, ethyl acetate, ethyllactate, ethyl oleate, glycerol, glycofurol (tetraglycol), isopropylmyristate, methyl acetate, methyl ethyl ketone, N-methyl-2-pyrrolidone,MIGLYOLs® (esters of caprylic and/or capric acids with glycerol oralkylene glycols, e.g., MIGLYOL® 810 or 812 (caprylic/caprictriglycerides), MIGLYOL® 818 (caprylic/capric/linoleic triglyceride),MIGLYOL® 829 (caprylic/capric/succinic triglyceride), MIGLYOL® 840(propylene glycol dicaprylate/caprate)), oleic acid, peanut oil,polyethylene glycol, propylene carbonate, 2-pyrrolidone, sesame oil,SOLKETAL ([±]-2,2-dimethyl-1,3-dioxolane-4-methanol), tetrahydrofuran,TRANSCUTOL® (diethylene glycol monoethyl ether, carbitol), triacetin,triethyl citrate, diphenyl phthalate, and combinations thereof.Additionally, if the composition is to be applied as an aerosol, e.g.for topical application, the solvent may be or may include one or morepropellants, such as CFC propellants like trichlorofluoromethane anddichlorofluoromethane, non-CFC propellants like tetrafluoroethane(R-134a), 1,1,1,2,3,3,3-heptafluoropropane (R-227), dimethyl ether,propane, and butane.

Particularly suitable solvents and/or propellants include benzylbenzoate, benzyl alcohol, triacetin, triethyl citrate, dimethylsulfoxide, ethanol, ethyl lactate, glycerol, glycofurol (tetraglycol),N-methyl-2-pyrrolidone, MIGLYOL® 810, polyethylene glycol, propylenecarbonate, 2-pyrrolidone, and tetrafluoroethane. Other possible solventsinclude perfluorodecalin, perfluorotributylamine, methoxyflurane,glycerolformal, tetrahydrofurfuryl alcohol, diglyme, and dimethylisosorbide.

In certain compositions, the selected solvent is at least water soluble,so that it will diffuse quickly into bodily fluids or other aqueousenvironment upon administration, causing the composition to coagulateand/or become more viscous. In another embodiments, the solvent is notcompletely miscible with water or bodily fluids so that diffusion of thesolvent from the composition, and the corresponding increase inviscosity of the composition, are slowed.

In still further compositions provided according to the presentinvention, the composition includes a material that is not miscible withthe HVLCM, such that when combined with the HVLCM singularly or incombination with a solvent for the HVLCM, the resulting compositionforms an emulsion. Such emulsions may contain the HVLCM in the dispersedphase, such as in the case of SAIB/MIGLYOL® mixtures that are emulsifiedin water or glycerol, or they may contain the HVLCM as a component ofthe continuous phase, such as in the case of an aqueous solution that isemulsified in the HVLCM or a solution of the HVLCM in a water immisciblesolvent.

D. Dosage Forms

The controlled release compositions of the present invention are in ageneral sense formed by the combination of the GnRH active agent with asuitable controlled release component, as described above, wherein theresulting composition provides for controlled release of the GnRH activeto establish a sustained mean steady state plasma concentration (C_(ss))of the active of at least about 1.5 ng/mL for a period of at least about48 hours when the composition is administered to a subject.

The particular formulation of the compositions of the present inventionis within the general skill in the pharmaceutical arts, when appliedusing the teachings of the present specification and claims. Thus,suitable dosage forms can be provided establishing therapeuticallyeffective plasma levels of the GnRH active for a period of at leastabout 48 hours in a subject after administration of the composition,wherein such plasma levels are substantially higher than those attainedby the use of commercially available GnRH, or GnRH analog medicamentscurrently employed in the medical arts. Such dosage forms can then beused to establish a sustained mean C_(ss) of the GnRH active on theorder of at least about 1.5 ng/mL for a period of at least about 48hours when the dosage form is administered to a subject, in some dosageforms, a sustained mean C_(ss) of the GnRH molecule or GnRH analog onthe order of at least about 2.0 ng/mL or more can be established, inother dosage forms at least about 2.5 ng/mL or more, and in yet furtherdosage forms, at least about 3.0 to 5.0 ng/mL or more. All of the dosageforms comprising the novel compositions of the present invention arecapable of providing these high plasma levels for a period of at leastabout 48 hours in the subject after administration, in some cases, theselevels can be established for a period of at least about a week or moreor at least about 2 weeks or more, and in yet further cases these plasmalevels are established for a period of at least about a month or more.

In certain preferred embodiments of the invention, the dosage form isproduced using a combination of the GnRH active and a polymer controlledrelease component. Thus, suitable dosage forms can be manufactured whena hydrophobic polymer controlled release component is co-polymerizedwith a hydrophilic polymer, or monomers, to yield a suitable copolymersystem, most preferably a block copolymer, or when the hydrophobicpolymer component is blended with a hydrophilic polymer to yield asuitable blended polymer system. The polymer system can be producedusing standard copolymerization techniques, such as graftcopolymerisation, polycondensation and polyaddition, optionally with anappropriate catalyst. These techniques can be carried out inconventional manner with regard to time and temperature. Alternatively,the polymer system can be produced using standard blending techniques ofpolymers or blending of copolymers, again carried out in conventionalmanner with regard to time and temperature for the procedure.

Within the polymer system itself, the hydrophobic and hydrophiliccomponents can be present in any suitable ratio, where the specificamount of each component is selected based on the relative degree ofhydrophobicity or hydrophilicity of each component, respectively. Suchdosage forms can be produced to exhibit monophasic or zero-order or nearzero-order release kinetics of the GnRH active agent.

In certain preferred compositions, the polymer system used as thecontrolled release component is a copolymer or a polymer blendcomprising a hydrophobic component selected from the group consisting ofpolyhydroxy acids, such as poly(lactide), poly(glycolide),poly(lactide-co-glycolide), poly(lactic acid), poly(glycolic acid), andpoly(lactic acid-co-glycolic acid), polyanhydride, polyorthoester,polyetherester, polycaprolactone, polyesteramide, polyphosphazine,polycarbonate, polyamide, or any copolymer thereof.

In certain other preferred compositions, the polymer system used as thecontrolled release component is a copolymer or a polymer blendcomprising a hydrophilic component selected from a poly(alkyleneglycol), polyvinyl pyrolidone (PVP), polyvinyl alcohol (PVOH),poly (alkyleneamine), poly (alkyleneoxide), or any copolymer thereof. Inthis regard, the hydrophilic component can be a poly (ethylene glycol)(PEG), and in certain cases, the hydrophilic component is a PEG havingmolecular weight of between about 700 Da and about 500 kDa.

In one specific embodiment, the polymer system used as the controlledrelease component is an AB block copolymer formed from poly(DL-lactide-co-glycolide) and PEG with a molecular weight of 750,wherein the PEG is present in the polymer system at about 1.25 wt %.

Once the suitable polymer system has been selected, the copolymerizationor polymer blending step can be conducted either prior to incorporationof the GnRH active agent into the composition, or at the same time. TheGnRH active agent is thus combined with the polymer controlled releasecomponent to produce the dosage form, using standard techniques. TheGnRH active can be combined with the controlled release component suchthat it will be present in the compositions of the present invention inamounts ranging from about 0.1 wt % to about 80 wt % and higher,although the GnRH active agent will typically be present in an amountranging from about 0.3 wt % to about 70 wt %, such as from about 10 wt %to 60 wt % or from about 20 wt % to about 55 wt %. The actual amountdepends upon the activity of the selected GnRH active, the dose desired,the duration of release desired, the administration frequency and othervariables. One skilled in the art will be able to ascertain effectiveamounts for selected GnRH actives by administration of the compositionand observing the desired therapeutic, pharmacological or diagnosticeffect. The exact amount of the GnRH active agent in the dosage form(composition) will thus be the amount necessary to achieve an effectiveconcentration of the active agent in vivo, for a given period of time.This amount varies with the type of GnRH medicament used, the desiredduration of the release, the target condition, desired administrationfrequency, the subject animal species and other factors. Preferably, thedosage forms will contain sufficient amounts of the GnRH active agentsuch that release of between about 0.10 ug/kg/day and 100 mg/kg/day willyield the desired effect. These parameters will be readily appreciatedby the ordinarily skilled artisan upon reading the instantspecification.

Depending upon the technique used to incorporate the GnRH active agentinto the controlled release component and thus form the dosage forms ofthe invention, the GnRH active agent may be distributed uniformly withinthe controlled release component (e.g., a polymer system), or may besubstantially encapsulated by the controlled release component. The GnRHactive may further be incorporated into the composition using anappropriate solvent system, either aqueous or non-aqueous, or the GnRHactive may be incorporated into the composition using a non-solventprocess.

In addition to incorporation of the GnRH active agent with thecontrolled release component, the dosage forms may further includepharmaceutically acceptable excipients such as diluents, preservatives,solubilizers, emulsifiers and/or carriers needed for administration. Theproportions in which a particular excipient may be present in the dosageform depends upon the purpose for which the excipient is provided andthe identity of the excipient. The optimal final pharmaceuticalformulation for a GnRH active agent of interest will be determined byone skilled in the art depending upon the route of administration anddesired dosage. Exemplary pharmaceutical compositions are disclosed inRemington's Pharmaceutical Sciences (1990) Mack Publishing Co., 18thEd., Easton, Pa.

In particular embodiments of the present invention, the above-describedpolymeric and non-polymeric controlled release components are used formanufacture of one or more compositions for controlled release of a GnRHmolecule or GnRH analog, useful in the treatment or amelioration of theconditions the GnRH active agent is intended to treat.

The compositions of the present invention can be provided as one or moresuitable dosage forms, depending upon the manner in which thecompositions will be administered. In this regard, the dosage formscomprising the compositions of the invention may be administered by oralroutes (e.g., as capsules such as hard capsules and soft capsules, solidpreparations such as granules, tablets, pills, troches or lozenges,cachets, pellets, powders, particulates, microparticulates (and anyother particulate form) and non-oral routes (e.g., as IM(intramuscular), SC (subcutaneous), transdermal, visceral, IV(intravenous), IP (intraperitoneal), intraarterial, intrathecal,intracapsular, intratumoral, perivascular, intracranial, intranasal,intrasinus, intrabladder, intravaginal, intraurethral, intrarectal,adventitial, injectable, pulmonary, inhalable, transmucosal, and othersuitable forms). In certain embodiments, the dosage forms are intendedfor administration via implantation, and are thus configured as a shapedarticle, such as a sphere, rod, slab, film, fiber, needle, cylinder,sheet, tube, or any other suitable geometry including microparticles,microspheres, and/or microcapsules. Such dosage forms can be providedany suitable size and shape of implantable device for specializedlocations, for example as a catheter, shunt, device for continuoussubarachnoid infusion, feeding tube, solid implant, uterine implant,periurethral implant, splint, or stent (formed from, containing orcoated with the composition). The dosage forms can be implanted at adesired site surgically, or using minimally invasive techniquesemploying trocars, catheters, etc. The implant can be implanted into anysuitable tissue using standard techniques, such as implantedintradermally, subdermally, subcutaneously, intraperitoneally,intramuscularly, or intralumenally (e.g., intraarterially,intravenously, intravaginally, and the like). The dosage forms canalternatively be fabricated as part of a matrix, graft, prosthetic orcoating. If an implantable dosage form is manufactured as a particulate,e.g., as a microparticle, microsphere or microcapsule, it can then beimplanted into suitable tissue using a cannula, needle and syringe orlike instrument to inject a suspension of the particles.

II. Methods of Manufacture

Tableting procedures, as well as formation of solutions, suspensions,emulsions, particles, microparticles, spheres, microspheres, films, etc.are all techniques well known in the pharmaceutical arts and within theskill of the general practitioner.

Methods for making fibrous polymeric dosage forms for delivery of activeagents are also well known in the art. See, e.g., Cowsar and Dunn,Chapter 12 “Biodegradable and Nonbiodegradable Delivery Systems” pp.145-162; Gibson, et al., Chapter 31 “Development of a Fibrous IUDDelivery System for Estradiol/Progesterone” pp. 215-226; Dunn, et al.,“Fibrous Polymers for the Delivery of Contraceptive Steroids to theFemale Reproductive Tract” pp. 125-146; Dunn, et al. (1985) “FibrousDelivery Systems for Antimicrobial Agents” from Polymeric Materials inMedication ed. C. G. Gebelein and Carraher, Plenum PublishingCorporation, pp 47-59. Any of these known methods, and numerous othermethods known in the art, may be employed in the practice of the presentinvention in order to produce fibrous dosage forms, comprising thecompositions of the present invention and having the unique featuresdescribed herein.

In addition, a variety of methods for processing polymer compositions byextrusion are described in Chris Rauwendaal (1994) “Polymer Extusion”Third Revised Edition, Carl Hanser Vertag, Munich, such as plasticatingextrusion, where the polymer composition is fed to the extruder as asolid, and melt-fed extrusion where molten polymer is fed to theextruder. As used herein, the terms “extrusion” or “melt-spinning”encompasses all these methods of manufacture. In melt-spinning, athermoplastic polymer is heated above its melting point, extrudedthrough an orifice, and cooled to form a filament. In one particularmethod for producing dosage forms containing the compositions of thepresent invention, a selected GnRH active agent is mixed with a polymercontrolled release component prior to extrusion and the mixture is thenground to form a feedstock for re-extruding the mixture to insureuniform mixing. Although generally formed in a geometry where thecross-section is a circle, such dosage forms can also be prepared withany other cross-sectional geometry, for example, an ellipsoid, a lobe, asquare, or a triangle. The composition can also be formed intomicroparticles, sheets, films or coatings, using standard processingtechnology.

Suitable dosage forms may be prepared in a variety of sizes depending onthe total dose of the GnRH active and the envisioned method and site ofadministration. In a certain composition, the dosage form is amonolithic rod with an overall diameter between 0.05 and 5.0 mm. Forsubcutaneous administration in humans, an overall diameter of between1.0 and 4.0 mm may be more preferred. The length of the device istypically between about 0.3 cm and 10 cm. For subcutaneous implantation,a more preferred length is between about 0.3 cm and 3.0 cm.

Drawing may used to produce extruded dosage forms, such as methods wherethe composition is passed around two or more sets of godets that areoperated at progressively faster speeds as the composition passesfurther down the line. The composition may pass through heated ovensbetween the godets so that the temperature can be carefully controlledto further influence the crystallinity of any controlled releasecomponents and excipients. Drawing may also be used to control the finaldiameter of the dosage form.

Because of the basic structure of dosage forms prepared by a continuousextrusion process, they can be provided in any length that is convenientfor handling. If the composition is sufficiently flexible, it can bewound onto a spool or into a coil and held in this way prior to cutting.Alternatively, the extruded composition can be collected as shorterlengths of perhaps a few centimeters or meters and held prior tocutting. It is also possible to cut the extruded composition to thefinished dosage form length as it is produced using a flywheel type ofcutter that is situated just downstream of the die.

The amount of the GnRH active agent to be incorporated and the amountused in the process will vary depending upon the particular agent, thedesired effect of the active agent at the planned release levels, andthe time span over which the agent should be released. Any of theabove-described processes can be used to incorporate more than one GnRHactive agent into a controlled release composition.

III. Methods of Use

It is an object of the invention to provide methods for establishingtherapeutically effective plasma levels of a GnRH molecule or GnRHanalog for about 48 hours or more in a subject. The methods generallyentail administering any one of the above-described controlled releasecompositions (as a suitable dosage form) to the subject such that, afteradministration, the administered composition provides a sustained meansteady state plasma concentration (C_(ss)) of the GnRH molecule or GnRHanalog of at least about 1.5 ng/mL for a period of at least about 48hours in the subject.

It is more particularly an object of the present invention to provide amethod suitable for establishing therapeutically effective plasma levelsof a GnRH molecule or GnRH analog for a period of at least about 48hours in a subject after administration of the composition, wherein suchplasma levels are substantially higher than those attained by the use ofcommercially available GnRH, or GnRH analog medicaments currentlyemployed in the medical arts. Accordingly, the methods of the presentinvention can be used to establish a sustained mean C_(ss) of the GnRHmolecule or GnRH analog on the order of at least about 1.5 ng/mL for aperiod of at least about 48 hours after the composition is administeredto a subject, in some particular methods, a sustained mean C_(ss) of theGnRH molecule or GnRH analog on the order of at least about 2.0 ng/mL ormore can be established, in other methods at least about 2.5 ng/mL ormore, and in yet further methods, at least about 3.0 to 5.0 ng/mL ormore. All of the novel methods of the present invention are capable ofproviding these high plasma levels for a period of at least about 48hours in the subject after administration. In some compositions, theselevels can be established for a period of at least about a week or moreor at least about 2 weeks or more, and in yet further compositions theseplasma levels are established for a period of at least about a month ormore.

The controlled release compositions, provided in the form of one or moredosage forms in accordance with the invention, can be administered usingany suitable procedure. Depending upon the particular GnRH active agentto be administered, the selected dosage form (size, shape, etc.) and theselected site of administration, the controlled release compositions canbe administered or implanted using minimally invasive procedures at asite where delivery is desired. These procedures can includeimplantation using trocars or catheters, injection using standard needleand syringes (of, e.g., powders, particles, microparticles,microspheres, microcapsules), ingrafting or surgical or non-surgicalplacement (of, e.g., a matrix, graft, prosthetic or coating), inhalation(of, e.g., powders or particulates), and the like. The compositions aredesigned so that the GnRH active agent is released in the desired dosageover a defined period of time. The compositions may further be designedso that they degrade during and after controlled release of the activeagent is achieved.

In certain aspects of the invention, the controlled release compositionis provided and administered as a single dosage form. For example, thecomposition can be provided as an implantable solid dosage form such asa rod. In other aspects, the composition is provided and administered asa plurality of dosage forms. For example, the compositions of theinvention can be provided as a combination of an implantable soliddosage form and an injectable depot. In certain other aspects, thecomposition is provided as a single dosage form that is administered asa single dosage unit, that is, a single dosage form is used to providethe recited sustained mean steady state plasma concentrations of theGnRH active. For example, a single solid implantable dosage form such asa rod can be administered to a subject to provide the desiredpharmacokinetics of the present invention. In other instances, multipledosage units of a single dosage form can be administered to provide therecited sustained mean steady state plasma concentrations of the GnRHactive, such as wherein a plurality (two or more) of solid implantabledosage forms are administered either simultaneously, concurrently, orsequentially to provide the desired pharmacokinetics of the presentinvention.

In yet further aspects of the invention, multiple dosage forms, eachrepresenting a single dosage unit, can be administered eithersimultaneously, concurrently, or sequentially to provide the desiredpharmacokinetics of the present invention. Whenever multiple dosageforms and/or units are administered, the actual dose of the GnRH activein each form or unit can be the same or different. In this way, anydesired sustained mean steady state plasma concentration of the GnRHactive can be achieved in a given subject by way of administering asingle dosage form and/or dosage unit of sufficient dose, or bycombining a plurality of dosage forms and/or units containing the sameor different dose of the GnRH active to tailor a specific dosesufficient to establish the desired plasma concentration in a givensubject.

In one particular embodiment, the controlled release composition isprovided in the form of multiple extruded solid implant rods, having aGnRH active loading of about 30 wt % relative to the total weight of thecomposition. The implants are administered subcutaneously atsubstantially the same or different sites on the subject using a trocarstyle administration device. The implants are left in place to provide asustained mean C_(ss) of the GnRH molecule or GnRH analog on the orderof at least about 1.5 ng/mL for a period of at least about 48 hoursafter the implants are administered to a subject. In some subjects, themethod is carried out to provide a sustained mean C_(ss) of the GnRHmolecule or GnRH analog on the order of at least about 2.0 ng/mL ormore, in other subjects at least about 2.5 ng/mL or more, and in yetfurther subjects, at least about 3.0 to 5.0 ng/mL or more. All of thesemethods are capable of being performed to provide high plasma levels fora period of at least about 48 hours in the subject after administration,in some cases, these levels can be established for a period of at leastabout a week or more or at least about 2 weeks or more, and in yetfurther cases these plasma levels are established for a period of atleast about a month or more, at least about 2 months or more, or even atleast about 3 months or more.

Any of the methods of the invention can be carried out to treat avariety of diseases and conditions, e.g., to treat hormone-dependentcancers (such as prostate cancer); to treat endometriosis; to treatearly puberty, to control estrogen production; to treat fertilityconditions; and the like.

In one embodiment, a controlled release composition is formulated toinclude a GnRH active as one or more solid implant dosage form. Thecomposition is then administered to a subject in order to target bloodlevel, production, function, or activity of a gonadotrophin LH or FSHsimilar to that occurring at or near the time of greatest reproductivefunction in the subject, which in humans corresponds to 18 to 35 yearsof age. For example, a normal blood level of LH around this time isapproximately 0-10.0 mIU/mL for males and approximately 0.4-92.9 mIU/mLfor females (which fluctuates with reproductive cycle). A normal bloodlevel of FSH around this time is approximately 2.0-22.6 mIU/mL for malesand approximately 2.9-29.5 mIU/mL for females (which also fluctuateswith reproductive cycle). Administration of the GnRH active implant issuitable to alter the blood level, production, function, or activity ofa gonadotrophin LH or FSH to achieve the desired level(s).

In another embodiment, a controlled release composition is formulated toinclude a GnRH active as one or more solid implant dosage form. Thecomposition is then administered to a subject in order to the targetblood level, production, function, or activity of LH or FSH to levelsthat are undetectable or nearly undetectable. For example, a blood levelof 0.7 mIU/mL for both LH and FSH is currently undetectable in aclinical laboratory.

In another embodiment of the invention, a controlled release compositionis formulated to include a GnRH active as one or more solid implantdosage form. The composition is then administered to a subject in orderto the target blood level, production, function, or activity of LH orFSH to levels as low as possible without unacceptable adverse sideeffects. An unacceptable adverse side effect is an adverse side effectthat, in the reasonable judgment of one of ordinary skill in the art,has costs that outweigh the benefits of treatment.

In the practice of these and other related methods, the subject's bloodlevel, production, function, or activity of LH or FSH may beperiodically monitored and the combinations, quantities, and dosageregimens of the LH/FSH-inhibiting agents may be titrated or varied inorder to achieve the target blood level, target production, targetfunction or target activity of LH and FSH. In a particularly preferredembodiment, the dosage for a GnRH active, for example leuprolideacetate, may be between approximately 0.01 mcg/kg/hour and approximately100 mg/kg/day, or other schedules that will be apparent to one ofordinary skill in the art, in light of this specification. In thesemethods, the subject may initially be administered a low dose, forexample approximately 0.01 mcg/kg/hour. After approximately two weeks,LH and FSH blood levels may be measured. If LH and FSH bloods levels arestill higher than the target, then the dose may be increased (forexample by 0.1 mcg/kg/hour). This titration can be repeated until theblood level, production, function or activity of LH or FSH reaches thedesired target blood level, production, function, or activity for LH orFSH, as set forth above.

For example, a 30 mg time-released dose of leuprolide acetate can beadministered to an adult male subject. The leuprolide acetate activeagent is provided in a biodegradable polymer controlled releasecomponent to supply a polymeric dosage form for controlled release ofthe GnRH active. The polymer component is a copolymer or a polymer blendcomprising a hydrophobic component and a hydrophilic component and thepolymer system does not form a hydrogel when contacted with, or immersedin an aqueous system, for example when the composition is implanted inthe subject. The leuprolide acetate active agent is incorporated withinthe polymer controlled release component to provide for controlledrelease of the agent from the composition. When the composition isadministered to the subject, for example, when it is implanted, thecomposition releases the GnRH active agent in a controlled fashion toprovide a sustained mean C, of the active agent on the order of at leastabout 1.5 ng/mL for a period of at least about 48 hours after thecomposition is administered to a subject. Release of the GnRH activepreferably occurs without a lag period, or with a minimal lag period. Inthis manner, the leuprolide can be gradually released over a period ofseveral months. After a period of two weeks, the subject's blood levelof LH may be undetectable and the subject's blood level of FSH may beapproximately 5 mIU/mL.

In another example, a dose of 1.88 mg time-released dose of leuprolideacetate can be administered to a subject. The leuprolide acetate activeagent is present in a composition formed with a biodegradable polymercontrolled release component to provide for controlled release of theGnRH active agent. The polymer is a copolymer or a polymer blendcomprising a hydrophobic component and a hydrophilic component and thepolymer system does not form a hydrogel when contacted with, or immersedin an aqueous system, for example when the composition is implanted inthe subject. When the composition is administered to the subject, forexample, when it is implanted, the GnRH active agent is released in acontrolled fashion to provide a sustained mean C_(ss) of the activeagent on the order of at least about 1.5 ng/mL for a period of at leastabout 48 hours after the composition is administered to a subject.Release of the GnRH active preferably occurs without a lag period, orwith a minimal lag period. In this manner, the leuprolide can begradually released over approximately one month, and is expected toreduce LH and FSH blood levels to undetectable levels in the subject. Itwill be apparent to one of ordinary skill in the art, in light of thisspecification, that in order to achieve this target, the dosage of theleuprolide active agent will vary from subject to subject in light offactors such as age, gender, body weight, diet, the disease beingtreated, the progression of the disease, and other drugs beingadministered.

Modifications and variations of the present invention will be obvious tothose skilled in the art and are intended to come within the scope ofthe appended claims.

1. A controlled release composition, comprising: (a) a GnRH molecule orGnRH analog; and (b) a controlled release component for controllingrelease of the GnRH molecule or GnRH analog from the composition,wherein said composition is capable of providing a sustained mean steadystate plasma concentration (C_(ss)) of the GnRH molecule or GnRH analogof at least about 1.5 ng/mL for a period of at least about 48 hours whensaid composition is administered to a subject.
 2. The composition ofclaim 1 wherein said composition is provided in a single dosage form. 3.The composition of claim 2 wherein said composition is further providedas a single dosage unit.
 4. The composition of claim 2 wherein saidcomposition is further provided as multiple dosage units.
 5. Thecomposition of claim 1 wherein said composition is provided in aplurality of dosage forms.
 6. The composition of claim 1, wherein thecomposition is provided as at least one implant dosage form.
 7. Thecomposition of claim 6, wherein the implant dosage form is a solid. 8.The composition of claim 7 wherein the implant dosage form is a fiber,needle, rod, sheet, film, particle or microparticle.
 9. The compositionof claim 6 wherein said implant is monolithic.
 10. The composition ofclaim 6, wherein the implant dosage form is injectable.
 11. Thecomposition of claim 10, wherein the implant dosage form is injectableto form a depot.
 12. The composition of claim 10, wherein the implantdosage form is injectable to form a solid or semi-solid implant.
 13. Thecomposition of claim 10 wherein the implant dosage form is a sphere or amicrosphere.
 14. The composition of claim 1, wherein the controlledrelease component comprises a polymer material.
 15. The composition ofclaim 14, wherein the GnRH molecule or GnRH analog is distributeduniformly within the polymer material.
 16. The composition of claim 14,wherein the GnRH molecule or GnRH analog is coated with the polymermaterial.
 17. The composition of claim 14, wherein the polymer materialof the controlled release component comprises at least one is materialselected from the group consisting of polyhydroxy acids, such aspoly(lactide)s, poly(glycolide)s, poly(lactide-co-glycolide)s,poly(lactic acid)s, poly(glycolic acid)s, and poly(lacticacid-co-glycolic acid)s, polyanhydrides, polyorthoesters,polyetheresters, polycaprolactone, polyesteramides, polyphosphazines,polycarbonates, polyamides, and copolymers thereof.
 18. The compositionof claim 1, wherein the controlled release component comprises anon-polymer material.
 19. The composition of claim 1, wherein thecontrolled release component provides for release of the GnRH moleculeor GnRH analog with linear or near zero order release kinetics.
 20. Thecomposition of claim 1, wherein the GnRH molecule or GnRH analog isreleased from the composition without a significant initial burst. 21.The composition of claim 20, wherein less than about 30% of the GnRHmolecule or GnRH analog is released from the composition within about 24to 48 hours of administration to a subject.
 22. The composition of claim1, wherein the GnRH molecule or GnRH analog is present in thecomposition in an amount of at least about 20 wt % relative to the totalweight of the composition.
 23. The composition of claim 1, wherein theGnRH molecule or GnRH analog is present in the composition in an amountof at least about 30 wt % relative to the total weight of thecomposition.
 24. The composition of claim 1, wherein the total amount ofthe GnRH molecule or GnRH analog in the composition is between about 5and 20 mg.
 25. A composition according to claim 1 capable of providing asustained mean steady state plasma concentration (C_(ss)) of the GnRHmolecule or GnRH analog of at least about 1.5 ng/mL for a period of atleast about 1 week when said composition is administered to a subject.26. A composition according to claim 1 capable of providing a sustainedmean steady state plasma concentration (C_(ss)) of the GnRH molecule orGnRH analog of at least about 1.5 ng/mL for a period of at least about 2weeks when said composition is administered to a subject.
 27. Acomposition according to claim 1 capable of providing a sustained meansteady state plasma concentration (C_(ss)) of the GnRH molecule or GnRHanalog of at least about 1.5 ng/mL for a period of at least about 1month when said composition is administered to a subject.
 28. Acomposition according to claim 1 capable of providing a sustained meansteady state plasma concentration (C_(ss)) of the GnRH molecule or GnRHanalog of at least about 2.0 ng/mL for a period of at least about 48hours when said composition is administered to a subject.
 29. Acomposition according to claim 1 capable of providing a sustained meansteady state plasma concentration (C_(ss)) of the GnRH molecule or GnRHanalog of at least about 2.5 ng/mL for a period of at least about 48hours when said composition is administered to a subject.
 30. Acomposition according to claim 1 capable of providing a sustained meansteady state plasma concentration (C_(ss)) of the GnRH molecule or GnRHanalog of at least about 5.0 ng/mL for a period of at least about 48hours when said composition is administered to a subject. 31-60.(canceled)
 61. A method for providing therapeutically effective plasmalevels of a GnRH molecule or GnRH analog for about 48 hours or more in asubject, said method comprising administering the controlled releasecomposition of claim 1 to the subject, whereby after administration,said composition provides a sustained mean steady state plasmaconcentration (C_(ss)) of the GnRH molecule or GnRH analog of at leastabout 1.5 ng/mL for a period of at least about 48 hours in the subject.62. A method for providing therapeutically effective plasma levels of aGnRH molecule or GnRH analog for about 1 week or more in a subject, saidmethod comprising administering the controlled release composition ofclaim 25 to the subject, whereby after administration, said compositionprovides a sustained mean steady state plasma concentration (C_(ss)) ofthe GnRH molecule or GnRH analog of at least about 1.5 ng/mL for aperiod of at least about 1 week in the subject.
 63. A method forproviding therapeutically effective plasma levels of a GnRH molecule orGnRH analog for about 2 weeks or more in a subject, said methodcomprising administering the controlled release composition of claim 26to the subject, whereby after administration, said composition providesa sustained mean steady state plasma concentration (C_(ss)) of the GnRHmolecule or GnRH analog of at least about 1.5 ng/mL for a period of atleast about 2 weeks in the subject.
 64. A method for providingtherapeutically effective plasma levels of a GnRH molecule or GnRHanalog for about 1 month or more in a subject, said method comprisingadministering the controlled release composition of claim 27 to thesubject, whereby after administration, said composition provides asustained mean steady state plasma concentration (C_(ss)) of the GnRHmolecule or GnRH analog of at least about 1.5 ng/mL for a period of atleast about 1 month in the subject.
 65. A method for providingtherapeutically effective plasma levels of a GnRH molecule or GnRHanalog for about 48 hours or more in a subject, said method comprisingadministering the controlled release composition of claim 28 to thesubject, whereby after administration, said composition provides asustained mean steady state plasma concentration (C_(ss)) of the GnRHmolecule or GnRH analog of at least about 2.0 ng/mL for a period of atleast about 48 hours in the subject.
 66. A method for providingtherapeutically effective plasma levels of a GnRH molecule or GnRHanalog for about 48 hours or more in a subject, said method comprisingadministering the controlled release composition of claim 29 to thesubject, whereby after administration, said composition provides asustained mean steady state plasma concentration (C_(ss)) of the GnRHmolecule or GnRH analog of at least about 2.5 ng/mL for a period of atleast about 48 hours in the subject.
 67. A method for providingtherapeutically effective plasma levels of a GnRH molecule or GnRHanalog for about 48 hours or more in a subject, said method comprisingadministering the controlled release composition of claim 30 to thesubject, whereby after administration, said composition provides asustained mean steady state plasma concentration (C_(ss)) of the GnRHmolecule or GnRH analog of at least about 5.0 ng/mL for a period of atleast about 48 hours in the subject.